Alteration of HERG current profile during the cardiac ventricular action potential, following a pore mutation

HERG is believed to encode the major sub-unit of the cardiac 'rapid' delaye d rectifier K channel (I-Kr). Both I-Kr and HERG exhibit marked inward rect ification at positive membrane potentials due to rapid inactivation and thi s is thought to influence significantly the contribution of the current to cardiac action potential (AP) repolarisation, We investigated directly the role played by rapid inactivation, by measuring current activated by a vent ricular AP waveform, from Chinese Hamster Ovary cells transfected with HERG cDNA with a point-mutation (S631A) in the pore region. Square command puls es elicited HERG-S631A current which increased progressively in magnitude w ith test potential up to +30/+40 mV (n=6), During test pulses to +40mV, HER G-S631A exhibited Little inactivation compared to wildtype HERG. During an action potential command, WT-HERG current developed progressively during th e AP plateau and slow repolarisation phase, showing maximal current between -30mV and -40 mV (n=10). In contrast, HERG-S631A current increased earlier during the AP plateau, with a maximal amplitude near +30mV (n=7). Current then declined as the AP proceeded, giving rise to a 'bow'- or 'inverted-U-' shaped current profile. A mathematical model with inactivation removed fro m the HERG current reproduced the I-V profile of HERG-S631A. These data pro vide a direct demonstration that rapid inactivation normally plays a critic al role in determining both time-course and voltage dependence of HERG/I-Kr -current during the cardiac ventricular AP. (C) 1998 Academic Press.